Cachexia, or severe tissue wasting, is an extremely debilitating consequence of cancer that results in nearly thirty percent of cancer deaths. The mechanisms underlying cancer cachexia remain poorly defined, but recent experiments have shed important new light on the role of critical mediators, which appear to alter the balance between protein synthesis and degradation in skeletal muscle. These experiments have demonstrated that genes involved in ubiquitin-mediated proteasomal degradation are dramatically induced in several in vitro models of skeletal muscle atrophy, in rodent models, and in patients. We will use a combination of genomic and proteomic approaches to identify both the key upstream regulators and downstream effectors of skeletal muscle atrophy, in particular in the context of cancer cachexia. This proposal will advance two important goals: (1) using genomics and a novel proteomic screen to identify key ubiquitin ligases and the substrates of these enzymes that are activated in both in vitro and in vivo murine models of cancer cachexia, simultaneously exploring the utility of in vitro models for identifying key pathways regulated during cancer cachexia, and (2) initiating an outline for key transcriptional regulators that drive expression of ubiquitin ligases during normal muscle differentiation and muscle wasting. If successful, our proposal will generate detailed information regarding mechanisms whereby ubiquitylation mediates the devastating effects of cachexia and suggest potential upstream regulators and downstream targets for therapeutic intervention. Lay Abstract Muscle wasting is an extremely debilitating result of cancer and results in the discomfort, and in many instances, death of the patient. Yet the mechanisms through which skeletal muscle wasting, or cachexia, occur are largely unknown. It is clear that protein modification (through attachment of a small molecule, ubiquitin) and degradation play a major role in this process, and this proposal aims to understand some of the important steps in muscle protein degradation that result in cancer cachexia. [unreadable] [unreadable] [unreadable] [unreadable]